Ischemic perinatal stroke (IPS) in humans is defined as cerebral ischemia that occurs from 20 weeks of gestation through the 28th postnatal day [
1]. The incidence of stroke in this age group ranks second only to the incidence in elderly persons, ranging between 1: 1600 and 1: 5000 [
1‐
3]. IPS can result in cerebral palsy, epilepsy, language development delay and other complications [
1,
2,
4]. The incidence of unilateral arterial cerebral infarction (ACI) in newborn infants is approximately 1:2300, and occurs most often in the middle cerebral artery (MCA) [
2]. The brains of mice on postnatal days (P)0–5 correspond to similar developmental stages to the brains of human pre-term fetuses at of gestation (< 32 weeks) [
5,
6]. Because of their small size and low body weight, the common carotid arteries and MCA in the mouse pups are small in diameter and fragile compared to those of adult mice, creating a surgical challenge that has proved insurmountable thus far. Thus, the youngest age in mice at which the MCA can be reversibly occluded by sutures is P9 [
5]. Although conventional MCA occlusion (MCAo) can be performed in P7 rats [
7‐
10], unfortunately MCAo is not feasible for mouse pups this young. However, it is highly desirable to model IPS in mice because they are the most commonly genetically edited species. Other approaches have therefore been developed for use in mouse pups, including common carotid ligation followed by a hypoxic episode [
11‐
13], ibotenate injection [
14] and dye-mediated photothrombosis (e.g. using Rose-Bengal or erythrosine B) [
15‐
17], but these procedures lead to global hypoxia or permanent focal occlusion and do not allow precise control of reperfusion in blood vessels, and some require overly invasive surgery. Thus, it remains challenging to produce transient focal ischemia in perinatal and neonatal mice to model IPS and study the resulting disruption of the neuron-glia-vasculature network. This study aims to implement and optimize SIMPLE technology [
18] to model IPS in perinatal and neonatal mice, thereby providing a convenient strategy to produce focal ischemia in mice of such young ages (see Scheme
1). We use magnetic nanoparticles to occlude the distal MCA (dMCA) of pups as early as P0. SIMPLE does not involve any arterial surgery in the brain, which obviates the difficulty of performing delicate surgery on pups [
6] and enables perinatal and neonatal stroke study in a manner that is convenient, potentially expand the scale of investigating IPS. Combined with genetically engineered mouse pups, it provides deep mechanistic insight into the pathology of IPS.